PD‐L1 inhibitors combined with whole brain radiotherapy in patients with small cell lung cancer brain metastases: Real‐world evidence

Abstract Background Numerous studies have demonstrated that brain metastases patients may benefit from intracranial radiotherapy combined with immune checkpoint inhibitors (ICIs). However, it is unclear whether this treatment is effective for patients with small cell lung cancer brain metastases (SCLC‐BMs). Methods We conducted a retrospective study by analyzing medical records of patients with SCLC‐BMs from January 1, 2017 to June 1, 2022. Data related to median overall survival (mOS), median progression‐free survival (mPFS), and intracranial progression‐free survival (iPFS) were analyzed. Results A total of 109 patients were enrolled, of which 60 received WBRT and 49 received WBRT‐ICI. Compared to the WBRT alone cohort, the WBRT‐ICI cohort showed longer mOS (20.4 months vs. 29.3 months, p = 0.021), mPFS (7.9 months vs. 15.1 months, p < 0.001), and iPFS (8.3 months vs. 16.5 months, p < 0.001). Furthermore, WBRT‐ICI cohort had a better response rate for both BMs. (p = 0.035) and extracranial diseases (p < 0.001) compared to those receiving WBRT alone. Notably, the use of WBRT before ICI was associated with longer mOS compared to the use of WBRT after ICI (23.3 months for the ICI‐WBRT group vs. 34.8 months for the WBRT‐ICI group, p = 0.020). Conclusion Our results indicated that WBRT combined with immunotherapy improved survival in SCLC‐BMs patients compared to WBRT monotherapy. Administering WBRT prior to ICI treatment is associated with improved survival outcomes compared to WBRT following ICI treatment, for patients with SCLC‐BMs. These findings highlight the significance of conducting further prospective researches on combination strategies of intracranial radiotherapy and ICI in SCLC‐BMs patients.


| INTRODUCTION
Small cell lung cancer (SCLC) is a malignant and aggressive tumor originating from the mucous membrane of the lungs or from the gland. 1 Patients with SCLC often have poor clinical outcomes due to the high risk of the cancer spreading to the brain.Within 2 years of diagnosis, almost 80% of SCLC patients experience brain metastases (BMs). 2 The median survival for patients with untreated SCLC-BMs is approximately 3 months. 3Most BMs from SCLC are multifocal, making whole brain radiotherapy (WBRT) the preferred treatment option for patients with SCLC BMs. 4 Previous researches have demonstrated that WBRT regimen improves the interval to central nervous system (CNS) progression in SCLC patients, with a median overall survival (mOS) of 5.2 months. 5Additionally, an analysis of the America National Cancer Database revealed that WBRT regimen was associated with a slight improvement in mOS for SCLC-BMs patients age 75 or older. 6ecent clinical trials have shown that the combination therapy of PD-L1 inhibitor and platinum-based etoposide chemotherapy regimen is the preferred treatment for extensive stage SCLC.The IMpower133 and CASPIAN trials have also demonstrated that this therapy prolongs mOS to approximately 12 months and reduces the risk of death by 30% and disease progression (PD) by 23%. 7,8dditional evidence revealed that patients benefited from the durvalumab regimen regardless of baseline BMs status, which suggested that PD-L1 inhibitors contribute to improved survival in SCLC-BMs patients. 8ased on preclinical findings, the brain transports cerebrospinal fluid containing immune cells via functional lymphatic vessels, and dendritic cells, T-cells, and tumor-associated macrophages invade the immune microenvironment of BM. 9 Noticeably, immunomodulatory molecules, such as PD-L1, have been detected within BMs originating from diverse tumor types. 10,11A pooled analysis of the Keynote 158 and Keynote 028 trials revealed an objective response rate (ORR) of 15.4% among a subgroup of 13 patients with baseline BM who received immunotherapy.During the pembrolizumab maintenance after first-line chemotherapy period, 22% of patients experienced BMs, with a mOS of 9.6 months, suggesting that ICIs were associated with survival benefits in SCLC-BMs patients. 12,13adiotherapy reprograms the tumor immune microenvironment through multiple mechanism and synergizes with immunotherapy. 14For instance, radiation can enhance the antitumor effect of immunotherapy by activating dendritic cells, increasing the density of tumorinfiltrating lymphocytes (TILs), and modulating PD-L1 expression. 157][18][19] Results from a meta-analysis also showed that radiotherapy combined with immunotherapy significantly outperformed radiotherapy alone in patients with lung cancer BMs. 20ccording to the results of a retrospective study, combined cranial radiotherapy and immunotherapy were correlated with improved survival benefits in patients with NSCLC, renal cell carcinoma (RCC) or melanoma intracranial metastases.The mOS was up to 18 months with cranial radiotherapy combined with immunotherapy. 21Briefly, the integration of radiotherapy and immunotherapy holds promising potential as a therapeutic approach, leading to improved survival outcomes in patients diagnosed with SCLC-BMs.However, the specific role of WBRT-ICI in SCLC-BMs and whether the WBRT-ICI regimen offers advantages over the WBRT alone in SCLC-BMs is still unclear.Therefore, we conducted this study to assess the survival outcomes of WBRT-ICI and WBRT alone in patients with SCLC-BMs, aiming to provide optimized treatment strategies for SCLC-BMs patients.

| Patients and eligibility criteria
A total of 109 patients with SCLC-BMs at two centers between January 1, 2017 and June 1, 2022 were enrolled.Among them, the patients of WBRT cohort were all from Shanghai Pulmonary Hospital, 10 patients in the WBRT-ICIs cohort were from Shanghai Chest Hospital, and the rest were from Shanghai Pulmonary Hospital.Inclusion criteria were: (1) pathologically confirmed small cell lung cancer; (2) the presence of BMs on cranial MRI; (3) sufficient information about follow-up and electronic medical records; (4) adopted WBRT-ICIs or WBRT treatment; (5) ≥18 years old; (6) received more than 3 cycles of immunotherapy; (7) extracranial lesions were stably controlled.Exclusion criteria were: (1) combined with other tumors; (2) received prophylactic cranial irradiation (PCI) or any type of surgery; (3) follow-up not completed; (4) death without imaging evidence of disease progression.The before group included sequential therapy (WBRT within 3 months prior to initial immunotherapy), and the after group include induction therapy (several rounds of immunotherapy followed by concurrent WBRT) and concurrent therapy (concurrent WBRT and immunotherapy).
The time period from the initial diagnosis of BMs until the date of death or the last follow-up, which occurred on January 30, 2023, was referred to as overall survival (OS).Progression-free survival was calculated from the start of immunotherapy to the date of progression disease (According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1) or was censored at the date of last CT when no progression had occurred.Available follow-up MRI imaging and reports were reviewed for new BMs, disease progression, leptomeningeal disease at most every 3 months per institutional practice until death, hospice enrollment, or leaving the hospital refusing any resuscitation.Intracranial progression-free survival (iPFS) was defined as the interval between WBRT and their earliest CNS progression or as the date at which they went on to have last MRI if there was no CNS progression (According to RANO-BM criteria: assessment of response to neurotumor BMs).RANO-BM criteria defined as pathologically confirmed or a clinician's decision to change treatment due to imaging progression of previously treated BMs.Follow-up MRIs were obtained at 1, 3, 6, 9, and 12 months and lesion volumes were calculated at all available time points.To determine intracranial disease response, the maximum diameter of the T1 enhanced portion of all lesions was measured in three orthogonal planes at the time of treatment and at each follow-up and the lesion volume was calculated as (length × width × height)/2.RANO-BM criteria were used to define complete response (CR), partial response (PR), disease stabilization (SD), and PD.
Our study was approved by the institutional review boards of the two participating centers, which granted an informed consent waiver.The protocol was approved by the Ethics Review Committee of Shanghai Pulmonary Hospital.The approval number is L22-304.The study followed the Declaration of Helsinki (as revised in 2013) and deidentified and anonymized all patient records prior to analysis.Figure 1 depicts the recruitment flow chart for the cohorts of patients.
F I G U R E 1 Flow chart of patients recruiting.

| Treatment regimen
All patients underwent WBRT.WBRT was performed with 3 Gy/time for 10 times, and the total dose in 2 weeks was 30 Gy.For the immunotherapy strategy, patients treated with PD-L1 inhibitors (atezolizumab: initially 1200 mg every 21 days × 4 cycles, then 1200 mg every 21 days for maintenance; durvalumab: initially 1500 mg every 21 days × 4 cycles, then 1500 mg every 21 days for maintenance). 4

| Statistical analysis
To compare clinical parameters between WBRT and WBRT-ICIs cohort, we used Fisher's exact test or chisquared test.An estimate of survival (mOS, mPFS, and iPFS) was determined by Kaplan-Meier, and comparisons were made using log-rank tests.To assess the relationship with mOS, we used Cox proportional hazards regression.
The association between factors and mOS were evaluated by Cox proportional hazards regression.SPSS 23.0 was used for all analyses.The significance level was set at p ≤ 0.05, and all p-values were based on a two-sided significance level.

| Descriptions of the patients' characteristics
The ultimate analysis included 109 patients with SCLC-BMs, including 60 patients in the WBRT cohort and 49 patients in the WBRT-ICI cohort.Table 1 presents the demographics and clinical characteristics of two groups.Patients were on average 61.2 ± 8.9 years old (range: 39-85 years old); 41.3% (45/109) were ≥ 65 years old.Only 6.4% (7/109) of the patients were female.A total of 101 patients (92.7%) had an ECOG-PS 0-1 and only eight (7.3%) had an ECOG-PS ≥2.The proportion of BMs greater than three was similar between the two cohorts.Most patients (88/109) had BMs with a maximum diameter of more than 1 cm.The proportion of Karnofsky performance status (KPS) score higher than 80 was 81.7% in WBRT group and 77.6% in WBRT-ICI group.The majority of patients had a Graded Prognostic Assessment (GPA) score of 0-2 (86/109), whereas 21.1% patients (23/109) were greater than 2. The patients of WBRT treated cohort were all exposed to platinum-based doublet chemotherapy.The mentioned characteristics were well equated between two groups.
Exploratory subgroup analysis found that effect size directions were consistent across age, sex, smoking status, ECOG-PS, numbers of BMs, max tumor diameter in centimeter, KPS score, GPA score, RPA score at WBRT, baseline neutrophil-to-lymphocyte ratio (NLR), platelet lymphoid ratio (PLR) as well as lymphocyte-to-monocyte ratio (LMR) subgroups (Figure 3).Patients with three BMs or less benefited from WBRT-ICI treatment with a prolonged OS (HR = 0.3, 95% CI 0.108-0.88)but there was no significant correlation between WBRT-ICI regimen and mOS in patients with more than three BMs lesions (HR = 0.724, 95% CI, 0.323-1.619).

| Tumor response
The best responses to treatment of extracerebral disease and the BMs of the included patients were presented in Figure 4.The proportion of CR in the brain was 24.5% in the WBRT-ICI cohort, which was higher than that seen in the WBRT cohort (11.6%).Moreover, higher progressive disease (PD) rate was observed in patients with WBRT (20%), compared to patients with WBRT-ICI (12.2%).
The tumor response of anti-tumor therapy was stratified as response group (CR and PR) and no response group (stable disease [SD] and PD).There was a significant difference of intracranial response rate between WBRT cohort and WBRT-ICI cohort (p = 0.035).Similarly, we found that the response rate of extracerebral disease in the WBRT-ICI cohort is statistically higher than that in WBRT cohort (p < 0.001; Table 2).

| Timing of radiotherapy
The enrolled patients were split into two groups based on the time window in which the WBRT was administered.There were 29 patients in the before group and 20 patients in the after group.A comparison of the clinical characteristics of the two groups can be seen in Table 3. Notably, a significant difference in median OS was seen between the before and after group (34.8 months vs. 23.3months, logrank p = 0.020; Figure 5A).According to these results, a delayed WBRT treatment was associated with a worse OS than an earlier WBRT treatment.The WBRT-ICI (before group) regimen demonstrated a non-significant superior efficacy on PFS (log-rank p = 0.167) and iPFS (log-rank p = 0.263) compared to the after group (Figure 5B,C ).

| DISCUSSION
WBRT combined with PD-L1 inhibitors for SCLC patients with BMs is promising and attractive.Retrospective data has shown that combining WBRT with ICI is significantly associated with better survival and tumor response in patients with SCLC-BMs.Furthermore, an earlier regimen of WBRT was found to be superior in terms of OS compared to a delayed group.However, there is limited available data on the efficacy of combining intracranial radiotherapy and PD-L1 inhibitors in SCLC-BMs patients.][24][25][26] To our knowledge, there is a randomized controlled trial investigating the efficacy of combining radiosurgery and nivolumab in BMs among various tumors, including SCLC, although no published data is available (NCT02978404).8][29] For example, researchers have published a study of 199 melanoma and NSCLC patients who received concurrent or non-concurrent ICI and radiotherapy, and noted that concurrent ICI and radiotherapy was associated with a lower proportion of PD and local recurrence. 19Claire M. reported a better OS and lower 1-year F I G U R E 3 Subgroup analysis of overall survival (OS).All patients diagnosed with small cell lung cancer brain metastases (SCLC-BMs).ECOG-PS, Eastern Cooperative Oncology Group performance status; GPA, Graded prognostic assessment; KPS, Karnofsky performance status; LMR, lymphocyto-to-monocyto ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocytopy ratio; RPA, recursive partition analysis.
cumulative incidence of neurologic death among 101 lung cancer and melanoma patients who received immunotherapy and stereotactic radiotherapy (SRS), compared to patients treated with SRS alone. 30Therefore, we conducted this study to explore the feasibility of combination of ICI and WBRT for SCLC-BMs patients.5][36][37] The predictive value of PLR and LMR in efficacy of immunotherapy has been reported in NSCLC, nasopharynx cancer, melanoma, RCC patients receiving immunotherapy or radiotherapy, [38][39][40] and could be an independent prognostic factor among patients receiving ICI.The prognostic value of LMR has also been demonstrated in patients with SCLC.In our cohort, patients with low PLR (≤300) and high LMR (≥3) seemed to have superior OS when treated with a combination of intracranial radiotherapy and ICI.These findings imply that PLR and LMR may be potential indicators of the effectiveness of combination therapy in SCLC-BMs patients receiving ICI plus intracranial irradiation.
Our results showed that the efficacy of WBRT-ICI on SCLC-BMs patients appears to be better when WBRT is performed before ICI (23.6 months for the before group vs. 12.0 months for the after group, log rank p = 0.04).Similar results were observed in previous studies.Results from 46 patients with melanoma-BMs who received SRS-Ipilimumab indicated that receiving intracranial radiotherapy before ICI is significantly related to lower 1year regional recurrence (69% for during ICI vs. 64% for before ICI vs. 92% for after ICI, p = 0.003) and longer 1year OS (65% for during ICI vs. 56% for before ICI vs. 40% for after ICI, p = 0.008). 41Moreover, Cohen-Inbar et al. demonstrated that the 1-year survival rate for intracranial radiotherapy administered during or prior to ICI and intracranial radiotherapy administered after ICI were 59% and 33%, respectively.Notably, the local recurrence-free duration was higher in the SRS during and before cohort than in the SRS after group as well (19.6 months in during and before ipilimumab cycles and 3 months in after ipilimumab cycles, p = 0.005). 42Additionally, according to the timing of intracranial radiotherapy, a meta-analysis divided 218 patients with BMs from different studies into three groups-ICI before SRS, ICI concurrent with SRS, and ICI after SRS.Pooled results demonstrated that ICI before SRS was associated with inferior 1-year OS. 43 Mechanistically, the release of antigens from dying tumor cells after intracranial radiotherapy may offer a synergistic antitumor effect with ICI. 14 It is worth noting that "abscopal effect" of radiotherapy rarely occurred before the use of ICI.After the application of immunotherapy, higher   rates of "abscopal effect" can be observed.As a result, we hypothesized that performing intracranial radiotherapy before immunotherapy can generate neoantigens that yield an "abscopal effect" which enhanced the anti-tumor efficacy. 44 multicenter retrospective study suggested that compared to WBRT, SRS improved OS (8.5 months for SRS vs. 5.2 months for WBRT, log-rank p<0.001). 45Clinical trials are ongoing to evaluate the efficacy of SRS and WBRT among SCLC-BMs patients (NCT03297788, NCT03391362).There is still more work to be done in figuring out the best treatment plan for SCLC-BMs patients, particularly for those who have brain oligometastases.Though it is the first studies examining the combination of WBRT and ICI for SCLC-BMs patients, the study's validity may be constrained by its retrospective nature and small sample size.The quality of the medical records and clinical assessments was limited by the retrospective design, so data on treatment-related adverse effects were insufficient.Therefore, prospective studies are urgently needed to further investigate the efficacy and safety of the combination of intracranial radiotherapy and ICI among the SCLC-BMs patients.
Our study was a retrospective analysis based on realworld data, in which we observed that a subset of patients with longer survival contributed to the prolonged median survival time in our cohort.This phenomenon may reflect the heterogeneity and complexity of the disease, as well as the individualized response to the treatment.However, our study had several limitations, such as the small sample size, the retrospective design, and the potential selection bias.Therefore, our findings need to be confirmed and validated in larger and prospective cohorts with more rigorous methodology and more representative population.

| CONCLUSIONS
In conclusion, WBRT combined with PD-L1 inhibitors exhibited a superior survival outcome in SCLC-BMs patients compared to WBRT alone.Of note, the administration of WBRT prior to ICI is associated with improved survival outcomes compared to WBRT following ICI treatment in patients with SCLC-BMs.More prospective studies are desired to verify the efficacy intracranial radiotherapy and ICI combining strategy in SCLC-BMs patients.

F I G U R E 4
Best objective tumor response of patients evaluated by RECIST 1.1 criteria.Bars indicated best response for patients.BM, brain metastases; CR, complete response; OB, outside of brain; PD, progressive disease; PR, partial response; SD, stable disease.

F
I G U R E 5 (A) Kaplan-Meier curve for overall survival (OS), (B) progression-free survival and (C) intracranial progression-free survival (iPFS), stratified by timing of WBRT.
Baseline demographic and clinical characteristics of patients with SCLC brain metastasis.
T A B L E 1